The K23 Award will support rigorous training for the development of a career as an independent translational investigator with a focus on the genetics of mitral valve prolapse (MVP) and its progression. The principle investigator has completed a fellowship in cardiology and advanced imaging at Beth Israel Deaconess Medical Center (BIMDC) and a fellowship in echocardiography at Massachusetts General Hospital (MGH). The candidate has gained expertise in linkage analysis studies and phenotypic-genotypic correlations. As a staff cardiologist at BIDMC, she is now seeking new skills in genetic epidemiology and genome-wide association studies (GWAS). She will have access to a state-of-the-art genotyping facility (FHS), and echocardiography laboratories (BIDMC and FHS). Her multidisciplinary mentoring team includes experts in GWAS (Dr Ramachandran), and valvular disease/echocardiography (Drs Manning and Levine). A Master of Public Health in Clinical Effectiveness (Harvard School of Public Health) will provide the coursework necessary for her academic success. Although MVP is the most common cause of isolated mitral regurgitation (MR) requiring surgical repair, little is known about the genetic determinants of MVP and its progression. To date, 3 loci for autosomal dominant MVP have been described on chromosomes 11, 16 and 13, but gene finding has proved elusive. In addition, while the prevalence of MVP in the community is 2-5%, the prevalence of familial MVP is unknown. In the chromosome 13 family, previously non-diagnostic morphologies often represent early stages of expression in gene carriers and share two salient features with fully diagnostic MVP: an anteriorly displaced coaptation point and posterior leaflet asymmetry. This proposal tests the hypotheses that early stages of MVP exist and can progress in the FHS community, and that MVP heritability is high. In addition, several MVP loci can be identified through a multicenter GWAS. To test these hypotheses, the candidate will: 1) Measure mitral leaflet coaptation height, displacement, thickness, and degree of MR by echocardiography in the FHS Offspring Cohort and in a hospital-based sample (BIDMC) at baseline and at available follow-up of 11-17 (FHS) and 5 years (BIDMC). 2) Evaluate the presence of MVP in Gen 3 individuals whose parents in the Offspring Cohort have MVP. High MVP heritability would lead to specific gene-finding strategies such as whole-exome analysis and clarify if routine screening of family members in the community is warranted. 3) Search for MVP loci using GWAS both in FHS and in other US and European cohorts (> 2500 MVP subjects) (Leducq MITRAL Network).
These aims represent crucial steps towards future gene-finding strategies and understanding of the variability of progression and clinical outcomes among MVP patients in the community, with the potential of developing therapeutic targets to prevent progression at an early stage.

Public Health Relevance

Mitral valve prolapse (MVP) is a common disorder occurring in 2-5% of the population, and characterized by displacement of one or both leaflets into the left atrium. Although MVP is the most common cause of isolated mitral regurgitation requiring surgical repair, little is known about the genetic mechanisms underlying its genesis and progression. Previous studies in families with MVP have shown that early, 'non-diagnostic' forms of MVP often represent early stages of expression in gene carriers. This proposal aims at identifying these 'prodromal' morphologies in the community, assessing their progression, and revealing the genetic determinants involved in the genesis of MVP. These represent crucial steps towards understanding of variability of progression and outcomes among MVP individuals, with the potential of developing therapeutic targets at an early stage.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL116652-03
Application #
8991503
Study Section
Special Emphasis Panel (ZHL1-CSR-X (O1))
Program Officer
Scott, Jane
Project Start
2014-01-17
Project End
2018-12-31
Budget Start
2016-01-01
Budget End
2016-12-31
Support Year
3
Fiscal Year
2016
Total Cost
$124,115
Indirect Cost
$8,140
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Le Tourneau, Thierry; Le Scouarnec, Solena; Cueff, Caroline et al. (2018) New insights into mitral valve dystrophy: a Filamin-A genotype-phenotype and outcome study. Eur Heart J 39:1269-1277
Bui, An H; Roujol, Sébastien; Foppa, Murilo et al. (2017) Diffuse myocardial fibrosis in patients with mitral valve prolapse and ventricular arrhythmia. Heart 103:204-209
Parwani, Purvi; Avierinos, Jean-Francois; Levine, Robert A et al. (2017) Mitral Valve Prolapse: Multimodality Imaging and Genetic Insights. Prog Cardiovasc Dis 60:361-369
Delling, Francesca N; Li, Xinjun; Li, Shuo et al. (2017) Heritability of Mitral Regurgitation: Observations From the Framingham Heart Study and Swedish Population. Circ Cardiovasc Genet 10:
Delling, Francesca N; Hassan, Zena K; Piatkowski, Gail et al. (2016) Tricuspid Regurgitation and Mortality in Patients With Transvenous Permanent Pacemaker Leads. Am J Cardiol 117:988-92
Delling, Francesca N; Rong, Jian; Larson, Martin G et al. (2016) Evolution of Mitral Valve Prolapse: Insights From the Framingham Heart Study. Circulation 133:1688-95
Levine, Robert A; Hagége, Albert A; Judge, Daniel P et al. (2015) Mitral valve disease--morphology and mechanisms. Nat Rev Cardiol 12:689-710
Delling, Francesca N; Rong, Jian; Larson, Martin G et al. (2015) Response to Letter Regarding Article, ""Familial Clustering of Mitral Valve Prolapse in the Community"". Circulation 132:e187-8
Dina, Christian; Bouatia-Naji, Nabila; Tucker, Nathan et al. (2015) Genetic association analyses highlight biological pathways underlying mitral valve prolapse. Nat Genet 47:1206-11
Delling, Francesca N (2015) Left Ventricular Ejection Index as a Marker of Early Myocardial Dysfunction in Primary Mitral Regurgitation: Novel or Old in Disguise? Circ Cardiovasc Imaging 8:e003995

Showing the most recent 10 out of 14 publications